Orexin, also known as hypocretin or orexin peptide, comprises orexin A and orexin B (or hypocretin-1 and hypocretin-2), which is a neuroendocrine hormone secreted by the hypothalamus and functioning in the central nervous system. Its main physiological functions comprise: 1. regulating feeding, orexin can significantly promote feeding, which is in a dose-dependent manner, and activates the neurons that regulate feeding; 2. involving in the regulation of energy metabolism, orexin can significantly increase the metabolic rate; 3. involving in sleep-wake regulation, orexin can inhibit rapid eye movement sleep, and extend wake time, block the role of orexin and can promote sleep; 4. involving in the endocrine regulation, orexin have a very significant effect on the endocrine pituitary hormones; 5. relating with a sense of reward, learning and memory; 6. promoting gastric acid secretion; 7. promoting an increase in drinking water; 8. raising blood pressure; 9. playing a role in the treatment of alcohol addiction, drug addiction, alcoholism, and the like (David C. Piper et al., The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats. Eur. J. Neuroscience, 2000, 12(2), 726-730).
Orexins play a biological role by binding to orexin receptor. Orexin receptor is a G-protein coupled receptor. There are two types, called OX1 and OX2 receptor respectively. They are only distributed in the brain tissue, and there are significant differences between the two distributions, wherein, OX1 receptors are mainly distributed in the ventromedial hypothalamic nucleus, paraventricular nucleus, the hippocampal formation, dorsal raphe nucleus and locus coeruleus area, and OX2 receptors are mainly distributed in the cerebral cortex, subthalamic, hypothalamic paraventricular nucleus and preoptic nucleus (Sakurai T. et al., Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 1998, 92(4), 573-585).
Orexins have very important significance for mammals, especially for humans, which widely participate in regulating activities of the central nervous system, and play an important role in the pathology. There are a great many types of neurological and psychiatric disorders and diseases associated with orexin and orexin receptor. Common neurological and psychiatric disorders and diseases of the central nervous system comprise depression, anxiety disorders, seasonal affective disorder, mania, bipolar disorder, obsessive-compulsive disorder, insomnia and fatigue resulting from jet lag, mental schizophrenia, seizures, panic attacks, depression, alcohol addiction, drug addiction, alcoholism, substance abuse, drug addiction withdrawal symptoms, insomnia, psychotic disorders, epilepsy, sleep disorders, sleep disorder, sleep apnea syndrome, mandatory eating disorders, fibromyalgia, stress, obesity, Parkinson's disease, senile dementia, cognitive disorders, memory disorders, premenstrual tension syndrome, migraine headaches, memory loss, Alzheimer silent disease or other disorders related with normal or pathological aging. These diseases have seriously affected the social stability and the quality of life of patients and their families, and some may even lead to death.
In view of this, currently, orexin receptor antagonists have become the research and development focus of drugs resisting to neurological and psychiatric disorders and diseases of the central nervous system.